PI3Ks are a family of lipid kinases that catalyze the phosphorylation of the membrane lipid phosphatidylinositol (PI) on the 3′-OH of the inositol ring to produce PI 3-phosphate [PI(3)P, PIP], PI 3,4-bisphosphate [PI(3,4)P2, PIP2] and PI 3,4,5-triphosphate [PI(3,4,5)P3, PIP3]. PI(3,4)P2 and PI(3,4,5)P3 act as recruitment sites for various intracellular signaling proteins, which in turn form signaling complexes to relay extracellular signals to the cytoplasmic face of the plasma membrane.
Eight mammalian PI3Ks have been identified so far, including four class I PI3Ks. Class Ia includes PI3Kα, PI3Kβ and PI3Kδ. All of the class Ia enzymes are heterodimeric complexes comprising a catalytic subunit (p110α, p110β or p110δ) associated with an SH2 domain-containing p85 adapter subunit. Class Ia PI3Ks are activated through tyrosine kinase signaling and are involved in cell proliferation and survival. PI3Kα and PI3Kβ have also been implicated in tumorigenesis in a variety of human cancers. Thus, pharmacological inhibitors of PI3Kα and PI3Kβ are useful for treating various types of cancer.
PI3Kγ, the only member of the Class Ib PI3Ks, consists of a catalytic subunit p110γ, which is associated with a p101 regulatory subunit. PI3Kγ is regulated by G protein-coupled receptors (GPCRs) via association with βγ subunits of heterotrimeric G proteins. PI3Kγ is expressed primarily in hematopoietic cells and cardiomyocytes and is involved in inflammation and mast cell function. Thus, pharmacological inhibitors of PI3Kγ are useful for treating a variety of inflammatory diseases, allergies and cardiovascular diseases.
Although a number of PI3K-gamma inhibitors have been developed, there is a need for additional compounds to inhibit PI3K-gamma for treating various disorders and diseases. Particularly desirable are those PI3K-gamma inhibitors with improved pharmacokinetic/pharmacodynamics behavior in vivo, such as, for example, those inhibitors which increase the exposure of the drug to the target tissue while minimizing nontarget effects. A greater exposure per unit dose decreases the off target exposure relative to the exposure at the target tissue. Often the dose limiting toxicities occur in organs involved in clearing the drug from the circulation or in the case of an orally administered agent, in the gastrointestinal tract (GI). Decreased clearance and improved bioavailability increases the Cmax in the plasma while limiting the Cmax in the elimination organs such as kidney, liver, and GI. Further, increased absorption and decreased clearance (improved bioavailability) frequently results in less variability between patients in terms of exposure, thereby also improving the safety profile of the administered agent. In addition, agents that demonstrate improved physical properties, such as, for example, higher aqueous solubility, are also desirable.